(19) United States
`(12) Patent Application Publication (10) Pub. No.: US 2014/0193533 A1
`(43) Pub. Date:
`Jul. 10, 2014
`ANTONY
`
`US 2014O193533A1
`
`(54)
`
`FORMULATION OF CURCUMNOIDS WITH
`ENHANCED BOAVAILABILITY OF
`CURCUMIN, DEMETHOXYCURCUMIN,
`BSDEMETHOXYCURCUMIN AND METHOD
`OF PREPARATION AND USES THEREOF
`
`(71)
`(72)
`
`Applicant: Benny ANTONY, Ankamaly (IN)
`Inventor: Benny ANTONY, Ankamaly (IN)
`
`(21)
`
`Appl. No.: 14/206,044
`
`(22)
`
`Filed:
`
`Mar 12, 2014
`
`(60)
`
`Related U.S. Application Data
`Continuation-in-part of application No. 14/094,725,
`filed on Dec. 2, 2013, which is a division of application
`No. 13/385,717, filed on Mar. 5, 2012, now Pat. No.
`8,623,431, which is a division of application No.
`12/926,985, filed on Dec. 21, 2010, now Pat. No.
`8,153,172, which is a division of application No.
`12/662,740, filed on Apr. 30, 2010, now Pat. No. 7,879,
`373, which is a division of application No. 1 1/635,599,
`filed on Dec. 8, 2006, now Pat. No. 7,736,679, which is
`a continuation of application No. PCT/IN05/00176,
`filed on May 30, 2005, Continuation-in-part of appli
`cation No. 13/674.249, filed on Nov. 12, 2012, which is
`a division of application No. 13/506,572, filed on Apr.
`30, 2012, now Pat. No. 8,329,233, which is a division
`of application No. 12/926,980, filed on Dec. 21, 2010,
`now Pat. No. 8,197.869, which is a division of appli
`cation No. 12/073,864, filed on Mar. 11, 2008, now
`Pat. No. 7,883,728, which is a continuation-in-part of
`application No. 1 1/635,599, filed on Dec. 8, 2006, now
`Pat. No. 7,736,679, Continuation-in-part of applica
`
`tion No. 13/645,031, filed on Oct. 4, 2012, which is a
`continuation of application No. PCT/IN11/00232,
`filed on Apr. 4, 2011.
`(60) Provisional application No. 61/794,175, filed on Mar.
`15, 2013.
`Foreign Application Priority Data
`
`(30)
`
`Apr. 5, 2010 (IN) ............................... 95OCHE2O10
`Publication Classification
`
`(2006.01)
`(2006.01)
`
`(51) Int. Cl.
`A63L/2
`A61E36/9066
`(52) U.S. Cl.
`CPC ............. A6 IK3I/12 (2013.01); A61 K36/9066
`(2013.01)
`USPC .......................................................... 424/756
`ABSTRACT
`(57)
`A formulation of curcuminoid mixture having curcumin,
`demethoxycurcumin and bisdemethoxycurcumin and an
`essential oil of turmeric having 45% Ar-turmerone. The for
`mulation gives enhanced bioavailability of bisdemethoxycur
`cumin, demethoxycurcumin and curcumin for up to 10 hrs.
`The curcuminoid mixture has curcumin, demethoxycur
`cumin and bisdemethoxycurcumin in a weight/weight ratio
`ranging from about 0.8:1:1 to about 1:1.1:1.2. A process of
`preparing a formulation of curcuminoid mixture having cur
`cumin, demethoxycurcumin and bisdemethoxycurcumin in
`0.8:1:1 to 1:1:1:1.2 weight/weight ratio and an essential oil of
`turmeric having 45% Ar-turmerone. A formulation for
`improved biological activity and bioavailability and tissue
`distribution of curcumin, demethoxycurcumin and bis
`demethoxycurcumin.
`
`SAB1011
`U.S. Pat. No. 10,945,970
`
`

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`Patent Application Publication
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`Jul. 10, 2014 Sheet 1 of 2
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`Patent Application Publication
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`Jul. 10, 2014 Sheet 2 of 2
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`

`

`US 2014/O 193533 A1
`
`Jul. 10, 2014
`
`FORMULATION OF CURCUMNOIDS WITH
`ENHANCED BOAVAILABILITY OF
`CURCUMIN, DEMETHOXYCURCUMIN,
`BSDEMETHOXYCURCUMIN AND METHOD
`OF PREPARATION AND USES THEREOF
`0001. This Application is a nonprovisional of U.S. Provi
`sional Application 61/794,175 filed Mar. 15, 2013, and a
`continuation-in-part of U.S. application Ser. No. 13/645,031
`filed Oct. 4, 2012, which is a continuation in part of PCT
`Application Serial No. PCT/IN2011/000232, filed Apr. 4,
`2011, which claims priority of Indian Provisional Application
`Serial No. 950/CHF/2010, filed Apr. 5, 2010, and a continu
`ation-in-part of co-pending U.S. application Ser. No. 14/094,
`725, filed Dec. 2, 2013, which is a divisional of Ser. No.
`13/385,717, filed Mar. 5, 2012, which is a divisional of Ser.
`No. 12/926,985 filed Dec. 21, 2010, which is a divisional of
`Ser. No. 12/662,740 filed Apr. 30, 2010, which is a divisional
`of U.S. application Ser. No. 1 1/635,599 filed Dec. 8, 2006,
`which is a continuation of PCT Application Serial No. PCT/
`IN05/00176, filed May 30, 2005, and a continuation-in-part
`of co-pending U.S. application Ser. No. 13/674.249, filed
`Nov. 12, 2012, which is a divisional of U.S. application Ser.
`No. 13/506.572, filed Apr. 30, 2012, which is a divisional of
`Ser. No. 12/926,980, filed Dec. 21, 2010, which is a divisional
`of Ser. No. 12/073,864, filed Mar. 11, 2008, which is a con
`tinuation-in-part of Ser. No. 1 1/635.599, filed Dec. 8, 2006,
`which is a continuation of PCT Application Serial No. PCT/
`IN05/00176, filed May 30, 2005, all of which applications are
`incorporated in entirety by reference.
`
`FIELD OF INVENTION
`
`0002 Disclosure relates to a formulation of curcuminoid
`mixture and essential oil of turmeric having 45% Ar-tur
`merone. The formulation gives enhanced bioavailability of
`bisdemethoxycurcumin, demethoxycurcumin in addition to
`curcumin for up to 10 hrs. The curcuminoid mixture com
`prises curcumin, demethoxycurcumin and bisdemethoxycur
`cumin in which curcumin ranges from about 0.8 to about 1.0
`part weight/weight, demethoxy curcumin ranges from about
`1.0 to about 1.1 part weight/weight and bisdemethoxy cur
`cumin ranges from about 1.0 to about 1.2 part weight/weight.
`In the curcuminoid mixture the ratio of curcumin, demethoxy
`curcumin and bisdemethoxy curcumin ranges from about
`0.8:1:1 to about 1:1.1:1.2 weight/weight ratio. The formula
`tion provides improved biological activity and bioavailability
`of curcumin, demethoxycurcumin and bisdemethoxycur
`cumin.
`
`BACKGROUND OF THE INVENTION
`0003 Turmeric is a spice grown in India and other tropical
`regions of Asia. It has a long history of use in herbal remedies,
`particularly in China, India, and Indonesia. Turmeric or “yel
`low root’ is a general term for plants and plant materials
`having a high content of curcuminoids, compounds that have
`a strong colouring effect and which are used extensively in the
`colouring of e.g. food products.
`0004 Curcumin, reddish orange and with two methoxy
`groups, is the principal curcuminoid of the popular Indian
`spice turmeric, which is a member of the ginger family (Zin
`giberaceae). Turmeric's other two curcuminoids are
`demethoxycurcumin, orange-yellow with one methoxy
`group, and bisdemethoxycurcumin, yellow and without a
`
`methoxy group. The curcuminoids are natural phenols that
`are responsible for the yellow color of turmeric.
`0005 Preparing solvent extracts of Curcuma plant mate
`rials, in particular rhizomes, provides an oleoresin compris
`ing an essential oil of turmeric and curcuminoids. The oleo
`resin may Subsequently be subjected to a crystallization step
`resulting in the obtainment of curcuminoid crystals of a rela
`tively high purity and a liquid part. Liquid part included
`essential oil of turmeric, flavouring compounds, any impuri
`ties that remained in solution and, curcuminoids that did not
`crystallize. Essential oil of turmeric is isolated from the liquid
`part by steam distillation. The residual material that remains
`after the above separation of curcuminoid crystals and essen
`tial oil of turmeric consists mainly of uncrystallized curcumi
`noids. This residue is generally disposed of as a waste product
`of the industrial process.
`
`SUMMARY
`
`0006. The disclosure provides a composition for enhanced
`bioavailability of curcumin, demethoxycurcumin and bis
`demethoxycurcumin. The composition includes a curcumi
`noid mixture and essential oil of turmeric. The curcuminoid
`mixture includes curcumin, demethoxycurcumin and bis
`demethoxycurcumin in a weight ratio of curcumin,
`demethoxycurcumin, bisdemethoxycurcumin of about 0.8:
`1:1 to about 1:1.1:1.2. The essential oil of turmeric includes
`about 45% Ar-turmerone. The weight ratio of the curcumi
`noid mixture to essential oil of turmeric ranges from about 1:3
`to about 99:1. In some embodiments the weight ratio of the
`curcuminoid mixture to essential oil of turmeric ranges is
`about 10:1. In some embodiments the weight ratio of the
`curcuminoid mixture to essential oil of turmeric ranges is
`about 12:1.
`0007. The disclosure provides a formulation which gives
`enhanced bioavailability of bisdemethoxycurcumin,
`demethoxycurcumin, and curcumin for up to 10 hrs.
`0008 Disclosure provides a process for obtaining cur
`cuminoid mixture with curcumin, demethoxycurcumin and
`bisdemethoxycurcumin blended with essential oil of turmeric
`having 45% Ar-turmerone. More specifically, the disclosure
`provides a process wherein the residue, previously consid
`ered as a waste obtained after the separation of essential oil
`and curcuminoids from oleoresin, is made useful by a silica
`impregnation method. The process results a curcuminoid
`mixture having curcumin, demethoxycurcumin and bis
`demethoxycurcumin in 0.8:1:1 to 1:1.1:1.2 weight/weight
`ratio.
`0009. In some embodiments, the ratio of the three cur
`cuminoid mixture obtained from waste obtained after the
`separation of essential oil and curcuminoids from oleoresin is
`about 10-90% of curcumin, about 6-70% of demethoxycur
`cumin and about 2-60% of bisdemethoxycurcumin.
`
`BRIEF DESCRIPTION OF THE DRAWINGS
`
`0010 FIG. 1 provides Table 1. Table 1 shows percentage
`inhibition of inflammation in carrageenan induced paw
`oedema model.
`(0011
`FIG. 2 provides Table 5. Table 5 provides bioavail
`ability of curcumin, demethoxycurcumin and bisdemethoxy
`curcumin in human Subjects following by administration of
`different extracts.
`
`

`

`US 2014/0193533 A1
`
`Jul. 10, 2014
`
`DETAILED DESCRIPTION
`0012. The disclosure provides a process wherein the resi
`due, previously considered as a waste obtained after the sepa
`ration of essential oil and curcuminoids from oleoresin, is
`made useful by a silica impregnation method. The process
`results a curcuminoid mixture having curcumin, demethoxy
`curcumin and bisdemethoxycurcumin in about 0.8:1:1 to
`about 1:1.1:1.2 weight/weight ratio. The disclosure provides
`a formulation of curcuminoid mixture having curcumin,
`demethoxycurcumin and bisdemethoxycurcumin in 0.8:1:1
`to 1:1.1:1.2 weight/weight ratio and an essential oil of tur
`meric having 45% Ar-turmerone. The formulation gives
`enhanced bioavailability
`of bisdemethoxycurcumin,
`demethoxycurcumin in addition to curcumin for up to 10hrs.
`0013 In some embodiments, the formulation provides a
`curcuminoid mixture having curcumin, demethoxycurcumin
`and bisdemethoxycurcumin ranging from about 0.8:1:1 to
`about 1:1.1:1.2 of a weight/weight ratio of curcumin:
`demethoxycurcumin:bisdemethoxycurcumin. This range of
`weight ratio of the curcumin, demethoxycurcumin and bis
`demethoxy curcumin is obtained by extraction of the cur
`cumin from a turmeric waste residue obtained after the
`extraction of curcuminoid crystals from turmeric rhizomes.
`The turmeric waste residue is obtained after the separation of
`essential oil and curcuminoid crystals from turmeric oleo
`resin. Curcuminoid mixture having curcumin, demethoxy
`curcumin and bisdemethoxycurcumin in 0.8:1:1 to 1:1.1:1.2
`weight/weight ratio when blended with essential oil of tur
`meric having 45% Ar-turmerone gives a formulation having
`improved biological activity and bioavailability of curcumin,
`demethoxycurcumin and bisdemethoxycurcumin, as com
`pared to biological activity and bioavailability of a formula
`tion having curcuminoid crystals alone, or a formulation hav
`ing curcuminoid crystals blended with 45% Ar-turmerone, or
`a formulation of curcuminoid mixture alone having a weight
`ratio of curcumin: demethoxycurcumin: bisdemethoxycur
`cumin ranging from about 0.8:1:1.
`0014. In one embodiment, the ratio of the three curcumi
`noid mixture obtained from waste after the separation of
`essential oil and curcuminoids from oleoresin is typically:
`about 10-90% curcumin, about 6-70% demethoxycurcumin
`and about 2-60% bisdemethoxycurcumin.
`0015 The volatile oil of turmeric was isolated by conven
`tional methods of steam distillation to isolate essential oils
`and is well known in the art.
`0016 Curcuminoids are isolated from waste or residue
`material. The waste or residue material is obtained after the
`separation of essential oil and curcuminoids from oleoresin,
`by silica impregnation method. The waste or residue material
`is passed through a silica column. The silica column is
`washed with methanol to obtain three methanol fractions.
`Methanol fractions 2 and 3 have a mixture of curcuminoids.
`The combination of methanol fractions 2 and 3 provides a
`curcuminoid mixture having curcumin, demethoxycurcumin
`and bisdemethoxycurcumin in a 0.8:1:1 to 1:1.1:1.2 weight/
`weight
`ratio
`of curcumin:demethoxycurcuminibis
`demethoxycurcumin.
`0017 Curcuminoid mixture and volatile oils of turmeric
`having 45% Ar-turmerone are mixed and blended to get a
`uniform product. The product has curcuminoid mixture in
`0.8:1:1 to 1:1.1:1.2 weight/weight ratio of curcumin to
`demethoxycurcumin to bisdemethoxycurcumin.
`0018. The disclosure provides a method of extracting cur
`cuminoid mixture in 0.8:1:1 to 1:1.1:1.2 weight/weight ratio
`
`of curcumin: demethoxycurcumin: bisdemethoxycurcumin
`from residue or waste after the separation of essential oil and
`curcuminoids from oleoresin of turmeric. The disclosure pro
`vides a method of extracting curcuminoid mixture from resi
`due or waste after the separation of essential oil and curcumi
`noid crystals from oleoresin of turmeric. The disclosure
`provides a concentrated solution prepared by solvent treat
`ment of dried turmeric rhizomes. This concentrated solution
`is also referred to as oleoresin. Curcuminoids are crystallized
`from the oleoresin, leaving behind a waste liquid which con
`tains essential oil. It is found that the waste liquid contains
`essential oil also contains curcuminoids, however in indus
`trial process the liquid can be referred to as “waste” as far as
`curcuminoid extraction is concerned because the liquid is
`discarded with no further extraction of curcuminoids is per
`formed from this liquid. The disclosure provides a method to
`extract essential oil of turmeric from this liquid industrial
`waste. The disclosure provides a method for extracting the
`curcuminoids from this liquid industrial waste. The disclo
`Sure provides a method of steam distilling essential oils from
`the waste liquid. After steam distillation of essential oil from
`the waste liquid, a residue is obtained. This waste residue is
`discarded as industrial waste. The disclosure provides a
`method to extract curcuminoids having a weight/weight ratio
`of curcumin:demethoxy curcumin: bisdemethoxycurcumin
`ranging from about 0.8:1:1 to about 1:1.1:1.2 from the waste
`residue.
`I0019. In some embodiments of the method of preparing
`curcuminoid mixture having a weight/weight ratio of curcu
`min:demethoxycurcumin: bisdemethoxycurcumin ranging
`from about 0.8:1:1 to about 1:1.1:1.2, rhizomes of turmeric
`are dried to form dried turmeric rhizomes. The dried turmeric
`rhizomes are powdered to form a dried turmeric rhizome
`powder. Ethyl acetate is added to the dried turmeric rhizome
`powder to obtain an ethyl acetate extract solution and a resi
`due. The residue is separated from the ethyl, acetate extract
`solution. The ethyl acetate extract solution is filtered. The
`solvent is stripped from the filtered ethyl acetate extract solu
`tion to form an ethyl acetate extract. The ethyl acetate extract
`is cooled to obtain crystals of curcuminoid and a liquid. The
`liquid includes essential oil of turmeric and curcuminoids that
`did not crystallize. The liquid is steam distilled to obtain
`essential oil of turmeric and a waste residue (also referred to
`as waste residue 2). The wasteresidue 2 is loaded, onto a silica
`column. The silica column is washed with methanol. Three
`fractions of methanol eluate are collected and referred to as
`Fraction 1. Fraction 2 and Fraction 3. Fraction 2 and Fraction
`3 are combined to obtain a combined methanol fraction.
`0020. The combined methanol fraction is concentrated
`under heat and vacuum to obtain a concentrated methanol
`fraction. The concentrated methanol fraction is dried to
`obtain a dried methanol extract The dried methanol extract is
`powdered to obtain a powder having a curcuminoid mixture
`of curcumin, demethoxycurcumin and bisdemethoxycur
`cumin in a weight ratio of curcumin:demethoxycurcumin:
`bisdemethoxycurcumin of about 0.8:1:1 to about 1:1.1:1.2. In
`Some embodiments of the method, other solvents including
`acetone, hexane, ethyl acetate and combinations thereof can
`be used instead of only the ethyl acetate solvent described
`above.
`0021. The essential oil is fractionated to obtain three frac
`tions. One of the fractions contains essential oil of turmeric
`having 45% Ar-turmerone.
`
`

`

`US 2014/O 193533 A1
`
`Jul. 10, 2014
`
`0022. The disclosure provides a method of preparing a
`formulation of curcuminoids in 0.8:1:1 to 1:1.1:1.2 weight/
`weight
`ratio
`of curcumin:demethoxycurcuminibis
`demethoxycurcuminandessential oil of turmeric having 45%
`Ar-turmerone. The curcuminoid mixture of curcumin,
`demethoxycurcumin and bisdemethoxycurcumin in a weight
`ratio of curcumin:demethoxycurcuminibisdemethoxycur
`cumin of about 0.8:1:1 to about 1:1.1:1.2, is suspended in
`water to form a suspension. Essential oil having 45% Ar
`turmerone is added to the Suspension to form a mixture. The
`mixture is homogenized to form slurry. The slurry is dried
`under heat and vacuum to form a uniform blend of formula
`tion. The formulation has curcuminoid mixture in 0.8:1:1 to
`1:1.1:1.2 weight/weight ratio of curcumin:demethoxycur
`cuminibisdemethoxycurcumin and an essential oil of tur
`meric having 45% Ar-turmerone. The slurry can be dried
`under heat and vacuum using, for example, a vaccumized
`desolventiser having a stirrer.
`0023. In one embodiment, a homogeneous mixture of cur
`cuminoid mixture and water is prepared by Suspending the
`curcuminoid mixture in about 3 to 5 times its quantity of
`water to form a Suspension. The Suspension is homogenized
`to obtain slurry. The slurry is dried under heat and vacuum to
`form a formulation having a homogeneous mixture of the
`curcuminoid mixture and water.
`0024. The disclosure provides a dosage form of the for
`mulation of curcuminoids in 0.8:1:1 to 1:1.1:1.2 weight/
`weight
`ratio
`of curcumin:demethoxycurcuminibis
`demethoxycurcuminandessential oil of turmeric having 45%
`Ar-turmerone. The disclosure provides a dosage form of the
`formulation of curcuminoids in 0.8:1:1 to 1:1.1:1.2 weight/
`weight
`ratio
`of curcumin:demethoxycurcuminibis
`demethoxycurcuminandessential oil of turmeric having 45%
`Ar-turmerone for oral administration. Dosage forms of the
`formulation are selected from the group consisting of the hard
`gelatin capsule, Soft gelatin capsule, tablet, Sachet, powder,
`paste, Solution, Suspension, emulsion, pills etc.
`0025. The disclosure provides a method of preparing a
`gelatin capsule having curcuminoids in 0.8:1:1 to 1:1.1:1.2
`weight/weight ratio of curcumin:demethoxycurcuminibis
`demethoxycurcuminandessential oil of turmeric having 45%
`Ar-turmerone by Suspending curcuminoid mixture in water to
`form a suspension. Then essential oil turmeric is added to the
`Suspension to form a mixture. Then, the mixture is homog
`enized to obtain a slurry. Then the slurry is dried under heat
`and vacuum to form a uniform blend of a composition having
`the curcuminoid and the essential oil of turmeric. Then the
`blend is filled into a gelatin capsule. Gelatin capsules are
`prepared by a capsule filling machine manufactured by Pam
`Pharmaceuticals, Mumbai, India.
`0026. In some embodiments, the weight ratio of the cur
`cuminoid mixture, which has a 0.8:1:1 to 1:1.1:1.2 weight/
`weight
`ratio
`of curcumin:demethoxycurcuminibis
`demethoxycurcumin, to the essential oil of turmeric ranges
`from about 1:1 to about 90:1. The curcuminoid mixture hav
`ing curcumin:demethoxycurcuminibisdemethoxycurcumin
`in a 0.8:1:1 to 1:1.1:1.2 weight/weight ratio is also referred to
`as curcuminoid mixture. In some embodiments, the weight
`ratio of the curcuminoid mixture to the essential oil of tur
`meric ranges from about 1:1 to about 3:1. The weight ratio of
`the curcuminoid mixture to the essential oil of turmeric can be
`varied from about 3:1 to about 99:1. In some embodiments,
`the weight ratio of the curcuminoid mixture to the essential oil
`of turmeric ranges from about 1:1 to about 70:1. In some
`
`embodiments, the weight ratio of the curcuminoid mixture to
`the essential oil of turmeric ranges from about 1:1 to about
`45:1. In some embodiments, the weight ratio of the curcumi
`noid mixture to the essential oil of turmeric ranges from about
`3:1 to about 50:1. In some embodiments, the weight ratio of
`the curcuminoid mixture to the essential oil of turmeric
`ranges from about 8:1 to about 25:1. In some embodiments,
`the weight ratio of the curcuminoid mixture to the essential oil
`of turmeric is about 90:7. In some embodiments, the weight
`ratio of the curcuminoid mixture to the essential oil of tur
`meric is about 90:8. In some embodiments, the weight ratio of
`the curcuminoid mixture to the essential oil of turmeric is
`about 90:9. In some embodiments, the weight ratio of the
`curcuminoid mixture to the essential oil of turmeric is about
`89:9. In some embodiments, the weight ratio of the curcumi
`noid mixture to the essential oil of turmeric is about 89:8. In
`one embodiment, the ratio is about 85:15. In another embodi
`ment, the ratio is about 92:8. In another embodiment, the ratio
`is about 95:5. In another embodiment the weight ratio is about
`10:1. In some embodiments, the weight ratio is about 1.2:1. In
`Some embodiments, the weight ratio of the curcuminoid mix
`ture to the essential oil of turmeric is about 1:2. In some
`embodiments, the weight ratio of the curcuminoid mixture to
`the essential oil of turmeric is about 2:1. In some embodi
`ments, the weight ratio of the curcuminoid mixture to the
`essential oil of turmeric ranges from about 1:3 to about 99:1.
`0027. Some embodiments provide a method of enhancing
`bioavailability of curcumin by administering the formulation
`of curcuminoid mixture and essential oil of turmeric. Some
`embodiments provide a method of enhancing bioavailability
`of demethoxycurcumin by administering the composition of
`curcuminoid mixture and essential oil of turmeric. Some
`embodiments provide a method of enhancing bioavailability
`of bisdemethoxycurcumin by administering the composition
`of curcuminoid mixture and essential oil of turmeric. Some
`embodiments provide a method of enhancing bioavailability
`of curcumin, demethoxy curcumin and bisdemethoxy cur
`cumin in a tissue by administering the composition of cur
`cuminoid mixture and essential oil of turmeric. Enhancement
`of bioavailability of curcumin is observed in tissues including
`lungs, heart, kidney, brain, liver, pancreas, stomach, intestine
`and skin. Enhancement of bioavailability of demethoxy cur
`cumin is observed in tissues including lungs, heart, kidney,
`brain, liver, pancreas, Stomach, intestine and skin. Enhance
`ment of bioavailability of bisdemethoxy curcumin is
`observed in tissues including lungs, heart, kidney, brain, liver,
`pancreas, stomach, intestine and skin.
`0028. Another embodiment of the present invention pro
`vides a formulation having a curcuminoid mixture in 0.9:1:
`1.1 weight/weight ratio of curcumin:demethoxycurcumin:
`bisdemethoxycurcumin and a ratio of curcuminoid mixture;
`essential oil of turmeric of about 10:1 or about 12:1 ratio. The
`essential oil of turmeric includes 45% Ar-turmerone. The
`formulation has anti-inflammatory activity.
`0029 Inflammation is a complex biological response of
`vascular tissues and immune cells to harmful stimuli, Such as
`pathogens, damaged cells, or irritants. It is characterized by
`five signs: redness, increased heat, Swelling, pain, and/or loss
`of function. Inflammation can be classified as either acute or
`chronic. Acute inflammation is the initial response of the
`body to harmful stimuli and is achieved by the increased
`movement of plasma and leukocytes (especially granulo
`cytes) from the blood into the injured tissues. A cascade of
`biochemical events propagates and matures the inflammatory
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`response, involving the local vascular system, the immune
`system, and various cells within the injured tissue. Prolonged
`inflammation, known as chronic inflammation, leads to a
`progressive shift in the type of cells present at the site of
`inflammation and is characterized by simultaneous destruc
`tion and healing of the tissue from the inflammatory process.
`0030. At present, the majority of medicines widely used as
`anti-inflammatory agents are nonsteroid anti-inflammatory
`drugs (NSAIDs) that have, as the mechanism of action, an
`inhibitory action on cyclooxygenases (COXs) that is involved
`in the biosynthesis of prostanoids. However, since prostanoid
`synthesis activity is present in various tissues in the living
`body and governs the homeostasis thereof, various side
`effects are induced when NSAID is administered. One test for
`inflammation is the C-reactive protein (CRP) measurement.
`Some clinicians are advocating including it routinely. The
`CRP test detects any inflammation, no matter where it is. A
`skinned knee, flu, arthritis and infections are common causes
`of elevated CRP. Anti-inflammatory activity of extracts/drugs
`can be evaluated in Small animals like rats and mice. A classic
`model is carrageenan induced paw oedema model in rats.
`Carrageenan is an irritant and produces inflammation in rats
`paw after injecting a small Volume into Sub-plantar region.
`The volume of paw increases within 30 minutes of injecting
`carrageenan which can be measured by a plethysmometer.
`Volume of paw should be measured at various time points
`alter carrageenan and test drug administration and should be
`compared with control.
`0031. An anti-inflammatory activity of formulation hav
`ing a curcuminoid mixture in about a 0.9:1:1.1 weight/weight
`ratio of curcumin:demethoxycurcuminibisdemethoxycur
`cumin (C:D:B) and essential oil of turmeric having 45%
`Ar-turmerone in about a 10:1 and about 12:1 ratios showed
`higher percentage inhibition of inflammation. A higher value
`of percentage inhibition indicates more anti-inflammatory
`activity. Whereas curcuminoid mixture having C:D:B in 0.9:
`1:1.1 W/w ratio and regular turmeric extract showed negative
`percentage inhibition of inflammation. A negative percentage
`inhibition indicates that test material did not showing anti
`inflammatory effect. Formulation of curcuminoid mixture
`having C:D:B in 0.9:1:1:1 ratio blended with essential oil of
`turmeric having 45% Ar-turmerone in 10:1 or in 12:1 ratios
`shows a decrease in inflammation from about 30 mins to
`about 24 hours.
`0032 Some embodiments provide a composition to
`decrease inflammation. The composition includes a curcumi
`noid mixture and essential oil of turmeric. The curcuminoid
`mixture includes curcumin, demethoxycurcumin and bis
`demethoxycurcumin in a weight ratio of curcumin:
`demethoxycurcuminibisdemethoxycurcumin
`of
`about
`0.8:1:1 to about 1:1.1:1.2. The essential oil of turmeric
`includes about 45% Ar-turmerone. Some embodiments pro
`vide a method to decrease inflammation by administering the
`composition of curcuminoid mixture and essential oil of tur
`meric. In some embodiments, the decrease in inflammation is
`observed from about 30 mins to about 24 hours following
`administration of the composition of curcuminoid mixture
`and essential oil of turmeric.
`0033 Some embodiments provide a composition to
`decrease Swelling. The composition includes a curcuminoid
`mixture and an essential oil of turmeric. The curcuminoid
`mixture includes curcumin, demethoxycurcumin and bis
`demethoxycurcumin in a weight ratio of curcumin:
`demethoxycurcuminibisdemethoxycurcumin
`of
`about
`
`0.8:1:1 to about 1:1.1:1.2. The essential oil of turmeric
`includes about 45% Ar-turmerone. Some embodiments pro
`vide a method of decreasing Swelling by administering the
`composition of curcuminoid mixture and essential oil of tur
`meric.
`0034. In some embodiments of the formulation having
`curcuminoid mixture having C:D:B in 0.9:1:1.1 ratio blended
`with essential oil of turmeric having 45% Ar-turmerone in
`10:1 or in 32:1 ratios, enhances bioavailability of curcumin,
`demethoxycurcumin and bisdemethoxycurcumin in the body
`tissues.
`0035. In another embodiment, the formulation of cur
`cuminoid mixture having C:D:B in 0.9:1:1.1 ratio blended
`with essential oil of turmeric having 45% Ar-turmerone in
`10:1 or in 12:1 ratios, enhances the bioavailability of cur
`cumin, demethoxycurcumin and bisdemethoxycurcumin in
`the blood for up to 10 hrs. After administering capsules hav
`ing a 10:1 weight ratio of curcuminoid mixture having C:D:B
`in 0.9:1:1.1 w/w ratio blended with essential oil of turmeric
`having 45% Ar-turmerone, the maximum, absorption for cur
`cumin was 102.6 ng/gm, for demethoxycurcumin 120.2
`ng/gm and for bisdemethoxycurcumin 140.7 ng/gm. After
`administering capsules having a 12:1 weight ratio of cur
`cuminoid mixture having C:D:B in 0.9:1:1.1 w/w ratio
`blended with essential oil of turmeric having 45% Ar-tur
`merone, the maximum absorption for curcumin was 118.1
`ng.gm, for demethoxycurcumin 125.1 ng/gm and for bis
`demethoxycurcumin 152.5 ng/gm. Treating Subjects with
`curcuminoid mixture having C:D:B in 0.9:1:1.1 w/w ratio
`shows low detection of curcumin, demethoxycurcumin and
`bisdemethoxycurcumin.
`
`EXAMPLES
`
`Example 1
`
`Method of Preparation of Regular Turmeric Extract
`0036. The rhizomes of turmeric (500 Kg) were dried. The
`dried turmeric rhizomes were powdered to form powdered
`turmeric. Ethyl acetate extraction of the powdered turmeric
`was performed. For the extraction, ethyl acetate (1500 L) was
`added to the powdered turmeric at 78°C. temperaturetor 1 hr.
`After ethyl acetate extraction a solution and a residue 1 were
`obtained. The residue 1 was separated from the solution and
`1500 titers of ethyl acetate was again added to the residue I for
`extraction at 78°C. temperature for 1 hr. The resultant residue
`was similarly extracted with ethyl acetate for three more
`times. The solution from each of the ethyl acetate extraction
`steps was combined and filtered. The solvent from the filtered
`Solution was stripped to form an extract. Then the extract was
`cooled to about 4°C. to obtain crystals of curcuminoid (20
`Kg) and a liquid. The crystals of curcuminoid were isolated
`from the liquid by filtration. The crystal of curcuminoid
`included mixture of curcumin, demethoxycurcumin and bis
`demethoxycurcumin. The crystals of curcuminoid were also
`referred to as regular turmeric extract.
`Example 2
`
`Preparation of Fractions of Essential Oil of Turmeric
`0037. The rhizomes of turmeric (500 Kg) were dried. The
`dried turmeric rhizomes were powdered to form powdered
`turmeric. Ethyl acetate extraction of the powdered turmeric
`was performed. For the extraction, ethyl acetate (1500 L) was
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`added to the powdered turmeric at 78°C. temperature for 1 hr.
`After ethyl acetate extraction a solution and a residue 1 were
`obtained. The residue 1 was separated from the solution and
`1500 liters of ethyl acetate was again added to the residue 1
`for extraction at 8° C. temperature for 1 hr.